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Pulmonary Immunobiology and Inflammation in Pulmonary Diseases

NHLBI Workshop Summary

Published in the Am J Respir Crit Care Med Vol 162. pp 1983-1986, 2000 Internet address: www. atsjournals. org

JAMES D. CRAPO, ALLEN G. HARMSEN, MICHAEL P. SHERMAN, and ROBERT A. MUSSON

The immune system of the respiratory tract faces disparate demands, and is a special environment in which antiinflammatory and inflammatory responses must take place. The lung appears to have adopted novel pathways of immune control in order to process foreign antigens in a manner that does not interfere with its primary biologic functions. Understanding the mechanisms that keep the pulmonary immune system and the associated inflammatory response in check and yet prepared to respond quickly to potentially deadly or disease-causing materials is important to developing knowledge-based approaches to intervention in many pulmonary diseases. Investigation of pulmonary defense mechanisms offers important opportunities to define not only lung homeostasis but also the activation pathways that lead to disordered inflammatory and immune responses, and their contribution to a variety of idiopathic or progressive and chronic lung diseases. A partial list of those diseases that need further investigation includes acute respiratory distress syndrome, asthma, bronchopulmonary dysplasia (BPD), emphysema, interstitial lung diseases, lung injury, and pulmonary hypertension.

The National Heart, Lung and Blood Institute sponsored a workshop on August 26- 27, 1999 to review the current state of knowledge and to discuss opportunities for the investigation of pulmonary immunobiology and inflammation and their contribution to pulmonary disease. This report summarizes the discussions that took place and the recommendations that were generated at the workshop. The major focus of the workshop was nonspecific (innate) and specific (acquired or adaptive) cellular components of the immune system as they uniquely function in the lung. The workshop did not address the acquired "humoral" immune system (e. g., immunoglobulin A activity in bronchoalveolar lining fluid) or innate mediators of lung inflammation and their inhibitors. In 1995, a National Institutes of Health conference did specifically report on mediator- related aspects of inflammation in the airways (1). The workshop was also not organized around specific pulmonary diseases (e. g., bronchopulmonary dysplasia, asthma, idiopathic fibrosis) in which the immune system plays a major role.

The First Line of Pulmonary Defense: Mucociliary Clearance

The upper respiratory tract removes the vast majority of inhaled particles, and turbulent airflow deposits most of these particles on the thin mucus/ serous coating of the nasopharynx. The highly efficient mucociliary clearance system acts to return most particulate matter to the posterior pharynx, where it is swallowed. Small concentrations of inhaled infectious agents and antigens that avoid removal by the mucociliary apparatus and reach the underlying upper and lower respiratory tract epithelium require processing by the immune system. The challenge to the pulmonary system is to accomplish further processing without an inappropriate inflammatory amplification. Infective agents or amounts of foreign antigenic material (up to 10 10 particles per day) reach the alveolar region (5 3 10 8 alveoli, with a surface area of about 100 m 2 ) on a regular basis, yet they do not usually signal a serious threat to the host.

Increased expression of endothelial nitric oxide synthase is observed in ciliated respiratory epithelium, Clara cells, and type II pneumocytes in pulmonary inflammation. Exhaled nitric oxide (NO) is also increased in a number of inflammatory diseases of the lung, and it is therefore interesting to note that NO enhances ciliary beat activity (2). Preventing injury to or revitalizing the epithelium of the conducting airways after endotracheal intubation, inhalation of toxins, and/ or exposure to infectious agents are important issues in need of additional research.

Cells of the Pulmonary Immune System

The lung is an anatomically complex organ with at least three distinct compartments, including the airways and airspaces, interstitium, and vasculature. The airways and airspaces include the nasal passages, the conducting airways of the lung, and the alveoli. It is not known how inflammatory and immune responses are targeted to these compartments. However, antigens and microorganisms can be processed and presented to local lymphatic tissues when they reach these compartments. The pulmonary immune system has distinct collections of lymphoid tissue along the respiratory tract, including the nasal-associated lymphoid tissue (NALT), bronchus-associated lymphoid tissue (BALT), and lymph nodes that receive drainage from the nose or lung (3- 6). The roles played by the NALT, BALT, and draining lymph nodes in the induction and expression of lung immunity are not entirely clear. Antibodies (e. g., IgA) and immune effector cells in the respiratory tract lining fluids interact with or immobilize inhaled antigens and microbes at the same time that the mucociliary clearance apparatus attempts to mechanically remove them.

Dendritic cells. The lung has a substantial population of dendritic cells that increase in number in response to various inflammatory stimuli (7) and about which little is known. Whether dendritic cells in the lung have unique characteristics, functions, and/ or locations is not known. Dendritic cell mobility, antigen recognition, and accessory molecules and their signaling pathways, as well as the effects of cytokines on their activity, have only been partly defined (5, 8, 9). Other pulmonary cells, such as B-lymphocytes, interstitial macrophages, epithelial cells, fibroblasts, fibrocytes, and endothelial cells can be antigen-presenting cells, but current thinking indicates that dendritic cells are the overwhelmingly important antigen-presenting cell in the lung. In the neonatal lung, however, prominent fibrocytes (10) may stimulate naive T cells (11), demonstrating the complexity of antigen-presenting cells in the pathogenesis of BPD. Thus, the antigen processing system of the lung has unique characteristics, but remarkably little is known about this critical step in immune modulation.

Alveolar macrophages. Alveolar macrophages (AM) are generally recognized as relatively poor antigen-presenting cells (12). Their primary response to an antigen is to process and clear the antigen without signaling for an inflammatory response to be amplified. In fact, some data would suggest that AM commonly function to inhibit amplification of immune pathways (13). Such behavior would allow AM to clear the normal amounts of antigenic particles or infective agents that reach the gas-exchanging regions of the lung without damaging the alveolar capillary membrane. Under normal conditions, clearance of most antigens appears to be accomplished without initiating an inflammatory response or activating host immune responses with subsequent disruption of the delicate alveolar capillary membrane. Thus, there is a need to understand how AM participate in the induction of an immune response. Answering the following questions might more fully address the role of these cells: How many bronchoalveolar macrophages must be stimulated in a defined region of an airway to provoke a proinflammatory response? How many receptors and coreceptors must be engaged per macrophage before a response occurs? Is there a hierarchy of receptors and/ or coreceptors wherein stimulation by a specific agonist initiates a more profound response than that induced by another agonist? Answers to these questions would help to better understand the role of macrophages in other organ systems, but may be particularly testable in pulmonary airways. Macrophages seem to have the ability to determine that one microorganism is more dangerous than another through the use of pattern-recognition receptors (14). It is not known how this occurs.

T-Lymphocytes. There are substantial populations of T cells in the lung (15), and these include gd T cells that are present in higher concentrations than in most other tissues (16). The lung also contains a relatively high number of CD4 2 /CD8 2 ab T cells. These 2/ 2 ab T cells are relatively rare in most other tissues, but can constitute as many as 20% of the lymphocytes residing in the lung. The high numbers of 2/ 2 ab T cells in the lung imply a function for these cells in host defense, but such a role has not yet been established. The lung also contains a substantial number of ab T cells that are either CD4 1 or CD8 1 cells. These cells are located within the airways, alveolar epithelium, and interstitium. The CD4 1 or CD8 1 ab T cells are thought to be relatively hyporesponsive, and have a decreased proliferative response to mitogen, but appear to be functional after undergoing a "learning process" (12). Even less is known about lymphocytes in the fetal and neonatal lung. It has been suggested that there are specific lung receptors for T cells that allow selective homing of circulating T cells back to the lung (11, 17). However, the mechanisms that mediate T-cell recruitment to the lung and determine whether these cells subsequently settle in the lung parenchyma or airways are not understood. How T cells, which are recruited to the lungs, are triggered to express their effector functions, and how these functions are downregulated, also is not known (18). Nor has it been determined how immunologic memory is expressed in the lung (whether it is locally or systemically mediated). Understanding immunologic memory in the lung is considered very important because it must be established in order for vaccination to be successful. There is no information about how inflammatory events in utero may influence the generation of memory T cells to regulate tolerance versus hyperreactivity. Studies of this process following birth and during infancy, a period when new antigen exposure occurs frequently, may be immensely valuable in understanding immunologic memory in the lung.

B lymphocytes. Although bronchoalveolar lavage fluids from humans and laboratory animals contain relatively few B lymphocytes, these cells are common in the lung interstitium (18). Production of antibodies by B cells in the respiratory mucosa and associated lymphoid tissues has been shown to be important in resistance to infectious diseases and in the pathogenesis of airway hyperresponsiveness (18). Less understood, however, are the antibody-independent functions of B lymphocytes in the respiratory tract. Recent studies have indicated that B lymphocytes function in resistance to influenza in a CD4 1 T-cell- dependent (19) as well as a CD4 1 T-cell- independent (20) manner. The lung is unique in that antigens can persist in the alveolar region for relatively long periods, and such preservation may provide unique pathways for activation of B lymphocytes, although little is known about this immune processing pathway. Thus, the role of B lymphocytes as either effector cells in the production of antibodies or as accessory cells in T-cell- mediated immunity needs to be explored.

Pulmonary Inflammatory Cells

When the infectious or antigenic burden in the lung becomes too great for quiescent processing, traditional immune cells and/ or other pulmonary parenchymal cells release mediators that recruit inflammatory cells, many of which are phagocytes. This section reviews discussions at the workshop of inflammatory phagocytes and the oxidant stress that these cells and inflammation create in the lung.

Neutrophils. The lung contains a large number of neutrophils, and most of these cells are marginated along the walls of the lung microvasculature. Just as the airways process inhaled infectious agents and antigenic material, so may the pulmonary circulation also function as a filter for microorganisms or antigens that enter the systemic circulation but are not removed by the liver. In humans, the relative roles of endothelium, pulmonary intravascular macrophages, neutrophils, or other pulmonary cells in the clearance and processing of microorganisms and antigens from the systemic venous blood are poorly defined.

The pattern of migration of neutrophils appears to be unique within the lung. The alveolar epithelial surface contains high concentrations of adhesion molecules, such as intercellular adhesion molecule-1, which are more concentrated near the junctions of alveolar type I epithelial cells and type II epithelial cells (21). Under normal conditions it is rare to find neutrophils in the pulmonary airways, and neutrophils that reach the alveolar surface are rapidly cleared, suggesting that under normal conditions the lung is designed to exclude neutrophils from its alveolar capillary membrane. Closely regulated neutrophil migration could be a useful mechanism for allowing neutrophils to conduct surveillance functions while preventing an inflammatory cascade from being inappropriately initiated on the alveolar gas-exchange surface. Mechanisms of neutrophil trafficking to the lung, through the lung, and out of the lung are not well defined. Trafficking of neutrophils involves a seemingly infinite number of adhesion molecules and chemoattractants, although the CXC chemokines may be emerging as major determinants of neutrophil recruitment in the lung.

Neutrophils are the secondary phagocytic defense when AM fail to protect the lung in adults. In neonates, the numbers and function of AM are reduced, and neutrophils are essential to host defense against bacteria (22). Neutrophils may also be important in ingesting and clearing damaged epithelium from the airways (23). The recent observation that neutrophils undergo apoptosis rather than necrosis in the airways and alveoli is essential to defining pulmonary inflammation and repair (24). The finding that corticosteroids delay neutrophil apoptosis but accelerate eosinophil apoptosis may be an unsuspected beneficial mechanism of steroid action in allergic diseases such as bronchial asthma (24). Consequently, there is incomplete understanding of the role of neutrophils in the defense, injury, and repair of the immature and mature lung.

Eosinophils, mast cells, and basophils. Although eosinophils, mast cells, and basophils were not extensively discussed at the workshop, eosinophils have been identified as playing important roles in the pathogenesis of pulmonary hypersensitivity diseases, lung parasitic diseases, lung injury, and fibrosis. As with that of neutrophils, the accumulation of eosinophils in the lungs is mediated by chemokines. Mast cells and basophils have also received interest in the pathophysiology of asthma, but the role of these phagocytes in lung diseases was not reviewed at the workshop. Investigations of the mechanisms of control and of the accumulation of these cells in the lung will enhance knowledge about the pathogenesis of lung diseases and pulmonary hypersensitivity.

Oxidative Stress and Its Control

The presence of inflammatory cells such as neutrophils or eosinophils in the lung is associated with increased oxidant injury. These phagocytes and other nonimmune and immune cells may release reactive oxygen and nitrogen intermediates that cause injury during inflammation. The lung is uniquely designed to control oxidative stress. Lung lining fluids are enriched in the antioxidant glutathione, which reaches levels as great as 100-fold higher than those found in other tissues or in plasma. The lung also has remarkably high levels of antioxidant enzymes. For example, there is a high level of extracellular superoxide dismutase in lung (25). Alveolar type II epithelial cells, particularly in response to inflammatory cytokines, secrete both NO and extracellular superoxide dismutase, the effect of which is to maintain proportionally high concentrations of NO or one of its active adducts in the alveolar interstitium and alveolar lining fluids. Under such conditions, NO is likely to suppress immune activation by reducing neutrophil mobility, adhesion, and activation (26). Alternatively, endogenous NO production may be associated with lung injury during exuberant or chronic inflammatory states (27). It is likely that damaging reactive nitrogen species other than NO are generated. The use of inhaled NO and oxygen exposure in the immature lung for prolonged periods may potentially increase lung injury (28). The clinical use of inhaled NO creates the need for additional research on oxidant stress states in the lung, and on the mechanisms of protection from injury during inhaled NO therapy. Discussion at the workshop acknowledged that little is known about antioxidant defenses against NO and other reactive nitrogen intermediates.

Immunomodulators in the Lung

The pattern of production and release of antiinflammatory and inflammatory mediators when the lung experiences potentially harmful stimuli is poorly understood. Complement was specifically discussed at the workshop, and it was concluded that a renewed research into the role of complement in pulmonary injury is needed. The roles of proinflammatory agonists, such as arachidonic acid metabolites (thromboxanes and leukotrienes), cytokines, and chemokines, were not the specific focus of the workshop. To a limited extent, they were discussed in the context of how they modulate specific immune cells in the lung. Biologic response modifiers, such as the E series prostaglandins, transforming growth factor-b, interleukin (IL)-10, and IL-1 receptor antagonist have expanded the knowledge of antiinflammatory agents working within the lung. Specifically mentioned at the workshop were an ever-increasing number of pulmonary cells (e. g., epithelial serous and Clara cells) and their secretory products (e. g., b-defensin and CAP-18, and CC10, respectively) that either limit the extent of inflammation or produce a profound inflammatory response. Many of the mediators in epithelial fluid, whether they are proteins or lipids, may interact to control the inflammatory response. The interactions of such substances with each other, and the different cell surface receptors involved in signaling by these mediators, require more investigation in order to define the unique immunobiology of the lung.

Immune System Characteristics That Are Unique to the Lung

There are many molecules and cells within the lung that are not thought of as part of the traditional immune system. It has become apparent that pulmonary epithelium, endothelium, smooth-muscle cells, and fibroblasts contribute to the initiation and resolution of inflammation in the lung. Time did not permit full discussion at the workshop of each of these "accessory" immune molecules or cells, but more attention should be paid to them in future investigations. An overview of selected topics that were discussed at the workshop is provided later in this report.

Surfactant. The type II pneumocyte is an alveolar epithelial cell that has strong resistance to oxidant injury and thereby maintains its ability to secrete surfactant. It is believed that type II pneumocytes have a diverse role in pulmonary immunobiology. For example, they are the source of surfactant proteins A and D, both of which are important molecules that regulate inflammation in the lung (29). Surfactant lipids suppress a variety of immune cell functions, most notably lymphocyte proliferation. Changes in lipid/ protein ratios on the lung surface may also be important in the immune status of the lung, but this is less well documented. More information is needed about the scavenger or surveillance functions of surfactant proteins. Other proteins secreted into bronchoalveolar lining fluid by epithelial serous cells or Clara cells, such as lactoferrin, b-defensin, CAP-18, and CC10, may have either pro-or antiinflammatory effects. For example, surfactant protein D and other proteins in bronchoalveolar fluid may work in concert with macrophages and epithelial cells to bind and remove inhaled endotoxin without the initiation of an inflammatory response (30-33).

Respiratory epithelial cells. A variety of epithelial cells in the respiratory system, specifically serous cells in the conducting airways, Clara cells in the smaller airways, and alveolar type II epithelial cells on the alveolar surface, have unique receptors, including those related to interactions with a 2 -macro-globulin. Such cells are also a potent source of cytokines in the lung, and secrete a variety of peptide/ protein antibiotics (30- 35). The role of such cells in modulating precise immune responses needs to be better defined, especially since epithelial cells are among the first types of cells to interact with foreign materials deposited in the lung.

Conclusion and Recommendations

The lung is recognized as a unique immunologic organ that appears to have adapted novel pathways of immune control in order to process foreign antigens in a manner that does not interfere with its primary biologic functions. This poorly understood area of lung defense offers extraordinary opportunities to define not only lung homeostasis but also the activation pathways that lead to disordered inflammatory and immune responses, and the contribution of these pathways to a variety of idiopathic or progressive and chronic lung diseases. Opportunities recommended for future investigation include:

1. Investigating how the lung determines whether induction of inflammation and/ or an immune response is appropriate for a specific foreign material that has entered the lung, and how these responses are limited once they have been induced.

2. Defining the unique functions of lung dendritic cells and macrophages in determining how antigens are processed in the lung.

3. Determining the mechanism responsible for unique neutrophil, monocyte, eosinophil, basophil, and lymphocyte trafficking in the lung and its compartments, and how pulmonary lymphocyte trafficking is controlled in both primary and memory immune responses.

4. Determining how environmental factors, prior lung injury, or previous pulmonary immune responses interact with genetically determined immune responsiveness to affect subsequent lung inflammatory and immune responses.

5. Delineating the maturation of the immune system in the lung, and the way in which environmental factors can affect this process and subsequent immune responsiveness later in life. 6. Defining unique relationships between lung structure and inflammatory or immune responses.

List of participants:
The authors wish to thank the participants of the workshop who provided important ideas embodied in this report. These participants included:
Joseph A. Bellanti, Washington, DC; Mary Ann Berberich, Bethesda, MD; Thomas J. Braciale, Charlottesville, VA; Victoria Camerini, Charlottesville, VA; Arturo Casadevall, Bronx, NY; F. Sessions Cole, St. Louis, MO; James D. Crapo, Denver, CO; Carroll E. Cross, Davis, CA; Jeffrey L. Curtis, Ann Arbor, MI; Claire M. Doerschuk, Boston, MA; Michael M. Frank, Durham, NC; Bruce A. Freeman, Birmingham, AL; Allen G. Harmsen, Saranac Lake, NY; Stanley J. Hazen, Cleveland, OH; Gary W. Hunninghake, Iowa City, IO; Dallas M. Hyde, Davis, CA; Steven L. Kunkel, Ann Arbor, MI; David B. Lewis, Stanford, CA; Mary F. Lipscomb, Albuquerque, NM; Thomas R. Martin, Seattle, WA; William J. Martin, II, Indianapolis, IN; Robert A. Musson, Bethesda, MD; Patricia Noel, Bethesda, MD; Robert North, Saranac Lake, NY; David A. Schwartz, Iowa City, IO; Michael P. Sherman, Davis, CA; Susan L. Swain, Saranac Lake, NY; Galen B. Toews, Ann Arbor, MI; Marsha Wills-Karp, Baltimore, MD; Christopher B. Wilson, Seattle, WA; Jo Rae Wright, Durham, NC.

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(Received in original form March 23, 2000 and in revised form June 20, 2000)
Workshop sponsored by the National Heart, Lung, and Blood Institute and held in Bethesda, Maryland, August 26- 27, 1999.

Correspondence and requests for reprints should be addressed to Robert A. Musson, Ph. D., Division of Lung Diseases, National Heart, Lung, and Blood Institute, 2 Rockledge Center, Suite 10018, 6701 Rockledge Drive, MSC 7952, Bethesda, MD 20892. E-mail: rmusson@nih.gov

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